1. Field of the Invention
The present invention relates to azole derivatives and salts thereof each having excellent antimycotic action and good aqueous solubility, and medicaments containing the derivatives or salts as an effective ingredient, respectively.
2. Description of the Related Art
A number of azole compounds having antimycotic action have already been known. Although the conventional azole compounds can be used as a dermatologic preparation for external use, their low solubility in an aqueous solvent disturbs formulation of them into an aqueous preparation such as orally administrable preparation or intravenously administrable preparation without any treatment.
It is therefore proposed to add a complex forming agent or a cyclodextrin derivative in order to obtain an aqueous preparation (European Patent Application Laid-Open No. 0440372).
Use of such an additive is however not preferred for suppressing the side effect to the minimum level and to make the azole derivative itself soluble in an aqueous solvent is desired.
An object of the present invention is therefore to provide a novel compound having both strong antimycotic action and excellent solubility in an aqueous solvent.
With the foregoing in view, the present inventors have synthesized a variety of novel azole derivatives and carried out an extensive investigation on their antimycotic action and solubility in an aqueous solvent. As a result, it has been found that the compounds represented by the below-described formula (1) satisfy both, leading to the completion of the present invention.
In one aspect of the present invention, there is thus provided an azole derivative represented by the following formula (1): 
wherein, R1 represents a phenyl group substituted with one or more than one halogen atom or a phenyl group substituted with a trifluoromethyl group; R2 and R3 each represents a fluorine atom or an alkyl group, or may be coupled together to form a lower alkylene group; and R4 represents an alkyl group, or salt thereof; and a medicament comprising the derivative or salt as an effective ingredient.
In another aspect of the present invention, there is also provided a pharmaceutical composition comprising an azole derivative represented by the above-described formula (1) or salt thereof; and a pharmaceutically acceptable carrier.
In a further aspect of the present invention, there is also provided use, as a medicament, of an azole derivative represented by the above-described formula (1) or salt thereof.
In a still further aspect of the present invention, there is also provided a method for treating infectious diseases, which comprises administering an azole derivative represented by the above-described formula (1) or salt thereof.
Since the azole derivatives or salts thereof according to the present invention exhibit excellent antimycotic action and at the same time, good solubility in an aqueous solvent, they are suited for an intravenously administrable preparation and orally administrable preparation.
In the azole derivative (1) of the present invention, examples of the halogen atom which is substituted for the phenyl group of R1 include fluorine, chlorine, bromine and iodine atoms, with fluorine atom being particularly preferred. As R1, a difluorophenyl or (trifluoromethyl)phenyl, particularly 2,4-difluorophenyl or 4-(trifluoromethyl)phenyl group is desired.
As the alkyl group of R2 or R3, linear or branched C1-5 alkyl groups are preferred and specific examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl and n-pentyl groups. As R2 and R3, fluorine atom and methyl group are preferred. It is more preferred that R2 and R3 represent the same group.
Preferred examples of the alkylene group formed through coupling of R2 and R3 include C2-5 alkylene groups and specific examples include ethylene, trimethylene, tetramethylene and pentamethylene, with an ethylene group (xe2x80x94CH2CH2xe2x80x94) being particularly preferred. When R2 and R3 are coupled into the alkylene group, they form a saturated cyclic hydrocarbon with the adjacent carbon atom.
Preferred examples of the alkyl group represented by R4 include linear, branched or cyclic C1-10 alkyl groups, with linear or branched C1-4 alkyl or C3-6 cycloalkyl groups being particularly preferred. Specific examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups, of which methyl, ethyl and cyclopropyl groups are most preferred.
Any pharmaceutically acceptable salt can be used as the salt of the azole derivative (1) of the present invention. Examples include hydrochloride, nitrate, hydrobromide, p-toluenesulfonate, methanesulfonate, fumarate, succinate and lactate.
The azole derivatives (1) of the present invention include those containing an asymmetric carbon atom so that they can exist as optically active substances. The racemic mixtures and optically active substances are all embraced in them. In addition, their solvates such as hydrates are also embraced in them.
The azole derivatives (1) or salts thereof can each be prepared, for example, in accordance with the following reaction scheme. 
wherein, Ra and Rb each independently represents a C1-6 alkyl group or a phenyl group which may contain a substituent, or Ra and Rb may form, together with a nitrogen atom bonded thereto, a ring such as morpholine ring, Rc and Rd each independently represents a hydroxy protecting group and R1 to R4 have the same meanings as described above.
Described specifically, the target azole derivative (1) can be prepared by reacting Compound (2) with Compound (3) to obtain Compound (4), oxidizing the resulting Compound (4) into Compound (5) and then, hydrogenating the resulting Compound (5).
This preparation process will next be described more specifically.
Compound (2) serving as a raw material is available, for example, by the process described in Japanese Patent Application Laid-Open No. Hei 3-223266, 9-227531, 11-240871 and 11-279160.
First, Compound (4) is prepared by reacting Compound (2) with Compound (3). Examples of the hydroxy protecting group of Rc or Rd of Compound (3) used here include a benzyl group which may be substituted with a halogen atom and C1-6 alkyl groups such as t-butyl. The benzyl group can be removed later by catalytic hydrogenation, while the C1-6 alkyl group can be removed under hydrolysis conditions. As a preferred example of Compound (3), dibenzyl diisopropylphosphoramidite (Ra, Rb=isopropyl, Rc, Rd=benzyl) commercially available from Sigma-Aldrich can be mentioned.
In the reaction between Compound (2) and Compound (3), a reaction solvent which does not adversely affect the reaction such as methylene chloride, chloroform or ethyl acetate can be used, with methylene chloride being particularly preferred.
Examples of the additive include 1H-tetrazole, 4-dimethylaminopyridine, tetrazole hydrobromide, 5-methyltetrazole hydrobromide and pyridinium hydrobromide.
The reaction is desirably conducted at room temperature or greater, of which the room temperature is more desired.
Compound (4) can be converted into Compound (5) by oxidation. Examples of the oxidizing agent usable here include m-chloroperbenzoic acid, aqueous hydrogen peroxide, peracetic acid, potassium permanganate and oxone. As the reaction solvent, a solvent not adversely affecting the reaction such as methylene chloride, chloroform or ethyl acetate is preferred, with methylene chloride being particularly preferred. The reaction is preferably conducted at temperature less than room temperature, with 0xc2x0 C. being more preferred.
The hydroxy-protected phosphate ester represented by the formula (5) is then hydrogenated in the presence of a catalyst, whereby the compound represented by the formula (1) can be obtained.
Examples of the catalyst in the reaction solvent include palladium carbon and Pearlsman""s catalyst.
The catalyst is used in an amount of 0.01 to 10 times the weight of Compound (5), with 0.1 to 1 time being preferred.
As a reaction solvent, those inert to the starting compound (5) are preferred. Examples include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, ethylene glycol, propylene glycol, glycerin and methyl cellosolve; ethers such as tetrahydrofuran, dioxane and dimethoxyethane; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; and dimethyl sulfoxide. They may be used either singly or in combination as a mixed solvent. The solvent particularly preferred among them is methanol.
The reaction temperature ranges from 0 to 100xc2x0 C., preferably 10 to 50xc2x0 C., reaction time ranges from 1 to 200 hours, preferably 5 to 48 hours, and reaction pressure ranges from atmospheric pressure to 300 psi, preferably 40 to 30 psi.
After completion of the reaction, the catalyst is removed and the solvent is distilled off, and the residue is purified by recrystallization, chromatography or the like means, whereby the invention compound represented by the formula (1) can be isolated.
The invention compound of the formula (1) can be converted into its pharmaceutically acceptable salt, for example, inorganic salt with hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or hydrobromic acid; or organic salt with fumaric acid, maleic acid, acetic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid or p-toluenesulfonic acid.
Since the invention compound (1) or salt thereof thus obtained exhibits excellent antimycotic action, has high safety, and exhibits high solubility in an aqueous solvent enough for permitting formulation into an intravenously administrable preparation or orally administrable preparation, it is useful as a medicament for the prevention or treatment of various mycotic infectious diseases of animals including human being.
The invention compound can be formulated into pharmaceutical compositions, particularly antimycotics, of various dosage forms such as tablets, granules, powders, capsules, suspensions, injections, suppositories, liquid preparations, creams and ointments in a conventional manner by adding a pharmaceutically acceptable carrier. A solid preparation is preferably prepared by adding, to the invention compound, an excipient and optionally, a binder, a disintegrator, an extender, a coating agent or sugar coating agent and then forming the resulting mixture into tablets, granules, capsules or the like in a conventional manner. An injection is preferably prepared by dissolving, dispersing or emulsifying the invention compound in an aqueous carrier such as distilled water for injection in advance; or pulverizing the invention compound into powder and reconstituting it as an injection upon use. Examples of the administration method of the injection include intravenous administration, arterial administration, intraperitoneal administration, subcutaneous administration and intravenous infusion. A dermatologic preparation for external use is preferably prepared by adding, to the invention compound, an oil base or emulsion base and then forming the resulting mixture into a suppository, liquid preparation, cream or ointment in a conventional manner.
The invention compound is administered at a daily dosage of 1 mg to 10 g, preferably 3 mg to 50 mg per adult in one to several portions.